The present invention relates to compounds having a high affinity for mitochondrial diazepam binding inhibitor receptor (MDR).
Benzodiazepine (BZ) receptors which are an acting site of anti-anxiety drugs are classified into 2 subtypes of central benzodiazepine receptor (CBR) located on GABAA receptor/chloride channel complex and MDR located on the central nervous system (glial cells) or adrenal glands (Clin. Neuropharmacol., 16, 401-417 (1993)). Recently, CBR agonists of which representative is diazepam are widely used as anti-anxiety drugs. However, since CBR agonists act directly on GABAA receptor/chloride channel complex, they cause an anti-anxiety action together with side-effects such as excessive sedation or psychic dependence. On the other hand, since MDR agonists act indirectly on GABAA receptor/chloride channel complex via synthesis of neurosteroids such as endogenous neuroactive steroids (endogenous anti-anxiety substances), they cause an anti-anxiety action, but do not cause side-effects such as psychic dependence or excessive sedation (J. Pharmacol. Exp. Ther., 267, 462-471, 1993; ibid., 265, 649-656, 1993).
Accordingly, there is a need of the development of therapeutic agents for diseases (obsessive disorders, panic disorders) on which the previous BZs do not have a satisfactorily therapeutic effect, and development of MDR agonists as anti-anxiety drugs which alleviate the side-effects as recognized in the previous BZs.
Furthermore, the compounds which act on MDR, in view of acting on GABAA receptors, have a possibility of use as therapeutical agents of sleeping disorders, epilepsy, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, recognition and learning disability or drug dependence (Progress in Neurobiology, 38, 379-395, 1992, ibid., 49, 73-97, 1996; J. Neurochem., 58, 1589-1601; Neuropharmacol., 30, 1435-1440, 1991). In addition, these compounds, in view of the physiological functions of MDR, have a possibility of use as therapeutic agents of cancer (Biochimica et Biophysica Acta, 1241, 453-470, 1995), lipid metabolism abnormality (Eur. J. Pharmacol., 294, 601-607, 1995), schizophrenia (Neuropharmacology, 35, 1075-1079, 1996), cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS (Abstracts of the fifth international conference on AIDS, p. 458, 1989), Alzheimer""s disease (Alzheimer Dis. Assoc. Disotd., 2, 331-336, 1988) or Huntington chorea (Brain Res., 248, 396-401, 1982).
Among the compounds having affinity for MDR, there are indole compounds disclosed in Japanese Translation of PCT publication (Kohyo) No. 6-501030.
As a result of extensive researches about compounds having a high affinity for MDR, the present inventors have found that the specific 1,2-dihydro-2-oxoquinoline derivatives meet the above object, thus the present invention has been accomplished. As stated above, while the indole compounds having an affinity for MDR are known, there are not reported 1,2-dihydro-2-oxoquinoline derivatives of the present invention which have an affinity for MDR.
The present invention is directed to a 1,2-dihydro-2-oxoquinoline derivative represented by Formula [I]: 
wherein Ar is a pyridyl group or a group represented by the formula: 
(wherein X3 and X4 are the same or different, and are each a hydrogen atom, a halogen atom, a C1-5 alkyl group, a C1-5 alkoxy group, a hydroxyl group or a trifluoromethyl group), Y is a nitrogen atom or CH, R1 and R2 are the same or different, and are each a hydrogen atom, a C1-10 alkyl group, a C3-15 alkoxyalkyl group or a C3-15 alkylaminoalkyl group, or R1 and R2 taken together with the nitrogen atom to which they are attached form a cyclic amino group, X1 and x2 are the same or different, and are each a hydrogen atom, a C1-5 alkyl group, a C1-5 alkoxy group or a halogen atom, or X1 and X2 taken together form an alkylenedioxy group, and n is an integer of 1 to 3, provided that Y is other than CH when all of R1, R2, X1, X2, X3 and X4 are hydrogen atoms; or a pharmaceutically acceptable salt thereof.
In the present invention, the halogen atom for X3 and X4 refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The C1-5 alkyl group for X3 and X4 refers to a straight or branched alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group and an isopropyl group. The C1-5 alkoxy group for X3 and X4 refers to a straight or branched alkoxy group, and examples thereof are a methoxy group and an ethoxy group. The C1-10 alkyl group for R1 and R2 refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a cyclobutyl group, a cyclopropylmethyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a cyclobutylmethyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a cyclohexyl group, a cyclopentylmethyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, a cyclohexylmethyl group, an octyl group, a nonyl group and a decyl group. The C3-15 alkoxyalkyl group for R1 and R2 refers to a straight, branched or cyclic C1-13 alkoxy-C2-14 alkyl group, and examples thereof are a methoxyethyl group, a methoxypropyl group, a methoxybutyl group, an ethoxyethyl group, an ethoxypropyl group, an ethoxybutyl group, an ethoxypentyl group, an ethoxyhexyl group, an ethoxyheptyl group, a propoxyethyl group, a propoxypropyl group, a propoxybutyl group, an isopropoxyethyl group and a cyclopropylmethoxyethyl group. The C3-15 alkylaminoalkyl group for R1 and R2 refers to a straight, branched or cyclic C1-13 alkylamino-C2-14 alkyl group, and examples thereof are a methylaminoethyl group, a dimethylaminoethyl group, a methylaminopropyl group, a dimethylaminopropyl group, a methylaminobutyl group, an ethylaminoethyl group, an ethylaminopropyl group, an ethylaminobutyl group, an ethylaminopentyl group, an ethylaminohexyl group, an ethylaminoheptyl group, an ethylaminooctyl group, a propylaminoethyl group, a propylaminopropyl group, a propylaminobutyl group, an isopropylaminoethyl group, a cyclopropylmethylaminoethyl group and a pyrrolidinoethyl group. Examples of the cyclic amino group which is formed by R1, R2 and the nitrogen atom to which they are attached are a pyrrolidino group, a piperidino group, a homopiperidino group, a morpholino group, a piperazino group, an N-methylpiperazino group and a 3,5-dimethylpiperazino group. The C1-5 alkyl group for X1 and X2 refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a pentyl group. The C1-5 alkoxy group for X1 and X2 refers to a straight, branched or cyclic alkoxy group, and examples thereof are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a cyclopropylmethoxy group, a pentoxy group and an isopentoxy group. The halogen atom for X1 and X2 refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the C1-5 alkylenedioxy group which is formed by X1 and X2 taken together are a methylenedioxy group, an ethylenedioxy group and an n-propylenedioxy group. In addtion, examples of the pharmaceutically acceptable salt in the present invention are salts with mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, or salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid or benzenesulfonic acid.
The compound of Formula [I] can be prepared by the following general preparation methods 1 to 3. In the following reaction formulae, Ar, Y, R1, R2, X1, X2 and n are as defined above, Y1 is a nitrogen atom or CH, R3 and R4 are the same or different, and are each a C1-5 alkyl group or a benzyl group, and X5 is a chlorine atom, a bromine atom or an iodine atom.
[General Preparation Method 1]
Step (A): A 1,2-dihydro-2-oxoquinolinecarboxylate ester derivative (1) can be reacted with an arylalkyl halide derivative (2) in an inert solvent, if necessary, by using a phase transfer catalyst in the presence of a base to give a 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarborboxylate ester derivative (3).
Examples of the inert solvent are alcohols (e.g. methanol or ethanol), ethers (e.g. 1,2-dimethoxyethane or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile, N,N-dimethylformamide, water and a mixture thereof. Examples of the phase transfer catalyst are quaternary ammonium salts (e.g. benzyltriethyl ammonium bromide) and crown ethers (e.g. 18-crown-6-ether). Examples of the base are inorganic bases (e.g. potassium carbonate, sodium hydroxide, sodium hydride or metallic sodium) and alcoholates (e.g. potassium t-butoxide or sodium ethoxide).
Step (B): The 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarborboxylate ester derivative (3) is hydrolyzed with a base or an acid in an inert solvent to give a 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative (4).
Examples of the inert solvent are alcohols (e.g. methanol or ethanol), ketones (e.g. acetone), ethers (e.g. 1,2-dimethoxyethane or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile, N,N-dimethylformamide and a mixture of these solvents with water. Examples of the base are inorganic bases (e.g. potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide). Examples of the acid are hydrochloric acid, sulfuric acid and phosphoric acid.
Step (C): The compound (6) of the present invention can be synthesized from the 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative (4) via the acid halide or mixed acid anhydride thereof.
The acid halide includes an acid chloride and an acid bromide, and for example, they can be obtained by reacting a halogenating agent (e.g. thionyl chloride, thionyl bromide, oxalyl chloride, carbon tetrachloridexe2x80x94triphenylphosphine or carbon tetrabromidexe2x80x94triphenylphosphine) in an inert solvent. Examples of the above inert solvent are ethers (e.g. tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile and N,N-dimethylformamide.
The mixed acid anhydride includes an anhydride of a carboxylic acid with a carbonic acid, and for example, it can be obtained by reacting a halocarbonate ester (e.g. ethyl chlorocarbonate or isobutyl chlorocarbonate) in the presence of an organic base (e.g. triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine) or an inorganic base (e.g. sodium hydride) in an inert solvent. Examples of the inert solvent are ethers (e.g. tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile and N,N-dimethylformamide.
The compound (6) of the present invention can be also obtained by the reaction of the 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative together with a condensing agent and an amine (5) in an inert solvent.
The condensing agent refers to a conventional amidating reagent such as, for example, diphenylphosphoryl azide, diethyl cyanophosphate, carbonyldiimidazole or carbodiimides of which representatives are N,Nxe2x80x2-dicyclohexylcarbodiimide and N-ethyl-Nxe2x80x2-dimethylaminopropylcarbodiimide hydrochloride. Examples of the inert solvent are ethers (e.g. 1,2-dimethoxyethane or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile and N,N-dimethylformamide. In this reaction, if necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, etc. can be added as an activating agent.
[General Preparation Method 2]
A 1,2-dihydro-2-oxoquinolinecarboxylic acid derivative (7) is amidated according to Step (C) to give a compound (8) of the present invention, which is then subjected to 1-arylalkylation according to Step (A) to give a compound (6) of the present invention.
[General Preparation Method 3]
Step (D): An isatoic anhydride derivative (9) is reacted with a malonate ester (10) in an inert solvent in the presence of a base to give a 4-hydroxy-1,2-dihydro-2-oxoquinolinecarboxylate ester derivative (11).
Examples of the inert solvent are alcohols (e.g. methanol or ethanol), ethers (e.g.,1,2-dimethoxyethane or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile, N,N-dimethylformamide, water and a mixture thereof. The base includes inorganic bases (e.g. potassium carbonate, sodium hydroxide, sodium hydride or metallic sodium) or alcoholates (e.g. potassium t-butoxide or sodium ethoxide).
Step (E): The 4-hydroxy-1,2-dihydro-2-oxoquinolinecarboxylate ester derivative (11) can be reacted with an amine derivative (5) in an inert solvent to give a compound (12) of the present invention.
Examples of the inert solvent are alcohols (e.g. methanol or ethanol), ethers (e.g. 1,2-dimethoxyethane or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g. chloroform or dichloromethane), acetonitrile, N,N-dimethylformamide, water and a mixture thereof.
The compounds of the present invention have a high affinity for MDR, and therefore they are useful as therapeutic or preventive drugs of central diseases such as anxiety, related diseases thereto, depression, epilepsy, sleeping disorders, recognition and learning disability or schizophrenia, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, drug dependence, cancer, lipid metabolism abnormality, cerebral infarction, AIDS, Alzheimer""s disease or Huntington chorea.